Human OX40 ligand (OX40L), a membrane bound member of the tumor necrosis factor superfamily, is primarily expressed on activated antigen-presenting cells, such as dendritic cells, and to a lesser degree, B cells. See Sugamura, K et al., Nature Reviews Immunology 4:420 (2004); Weinberg A D, Trends Immunol. 23(2): 102 (2002). OX40L, also known as ACT-4 receptor, TNF4-Human, GP34 and CD134L, binds to the OX40 receptor (OX40), which is also called CD134, ACT-4, CD134 antigen, ACT35 antigen, and TNR4-Human. OX40 is a T-cell activation protein that is expressed following T-cell receptor (TCR) engagement. Engagement of CD40 by activated antigen-presenting cells increases the expression of OX40L. Engagement of OX40 by OX40L is co-stimulatory to effector T cells, and costimulation up-regulates the production of cytokines by T helper 1 and T helper 2 cells. OX40-OX40L interactions are also important for the generation of memory T cells, promoting the survival of effector T cells after antigen priming. Blocking OX40L in vivo reduced the severity of rheumatoid arthritis, experimental autoimmune disease (EAE), acute graft-verses-host disease (GVHD), inflammatory bowel disease, experimental leishmaniasis and collagen-induced arthritis in animal models. See Sugamura, K et al., Nature Reviews Immunology 4:420 (2004); Weinberg A D, Trends Immunol. 23(2): 102 (2002).
Anti-OX40L and antibodies recognizing OX40L are mentioned in, e.g. in WO 95/12673; WO 95/21915; WO 99/15200; Baum, P. R., et al., EMBO J. 13 (1994) 3992-4001; Imura, A., et al., Blood 89 (1997) 2951-2958; Imura, A., et al., J. Exp. Med. 183 (1996) 2185-2195; Kjaergaard, J., et al., J. Immunol. 167 (2001) 6669-6677; Lane, P., J. Exp. Med. 191 (2000) 201-206; Mallett, S., and Barclay, A. N., Immunol. Today 12 (1991) 220-223; Mallett, S., et al., EMBO J. 9 (1990) 1063-1068; Ndhlovu, L. C., et al., J. Immunol. 167 (2001) 2991-2999; Oyhshima, Y., et al., J. Immunol. 159 (1997) 3838-3848; Rogers, P. R., et al., Immunity 15 (2001) 445-455; Stüber, E., and Strober, W., J. Exp. Med. 183 (1996) 979-989; Stüber, E., et al., Gastroenterology 115 (1998) 1205-1215; Takahashi, &., et al., J. Virol. 75 (2001) 6748-6757; Takasawa, N., et al., Jpn. J. Cancer Res. 92 (2001) 377-382; Taylor, L., and Schwarz, H., J. Immunol. Meth. 255 (2001) 67-72; Weinberg, A. D., et al., Nature Medicine 2 (1996) 183-189; Weinberg, A. D., et al., Semin. Immunol. 10 (1998) 471-480; Weinberg, A. D., Trends Immunol. 23 (202) 102-109; Wu, T., et al., Transplant. Proc. 33 (2001) 217-218; Higgins, L. M., et al., J. Immunol. 162 (1999) 486-493; Yoshioka, T., et al., Eur. J. Immunol. 30 (2000) 2815-2823; and Wang, Q., et al. Tissue Antigens 64:566-574 (2004). Mouse anti-human OX40L antibodies are commercially available from MBL International Corp. (TAG-34) and R and D Corp (clones 159403 and 159408).
It is clear that there continues to be a need for agents that have clinical attributes that are optimal for development as therapeutic agents. The invention described herein meets this need and provides other benefits.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.